Malignant melanoma is a devastating disease with increasing incidence. While primary tumors can be successfully removed surgically, there is no satisfactory treatment for metastatic melanoma. This project employs a novel approach to radioimmunotherapy (RIT) of melanoma that takes advantage of the rapid growth of melanomas and the high cell turnover and lysis that releases melanin pigment. Melanin pigment can be targeted for delivery of cytotoxic radiation by a radiolabeled melanin-binding monoclonal antibody (mAb) generated against melanin and radiolabeled human melanin-binding peptides. This approach is highly selective for malignant melanoma because melanin in normal tissue is not accessible to the peptides and mAbs by virtue of its intracellular location. The objectives of this proposal are two-fold: to optimize immunoconjugates for stabilization of Re-188 and for convenience of Re-188 radiolabeling and to demonstrate the application of radiolanthanides for therapy of melanoma. Fulfillment of these objectives will provide an understanding of the relationship of beta energies and half-lives of radionuclides to therapeutic efficacy of melanoma, thus facilitating clinical introduction of RIT of metastatic melanoma. Moreover, the concepts that are learned from this project can be translated to other types of radiotherapy. The overall objectives are gathered into three specific aims. Specific aim 1 addresses identification of features of ligands that lead to improved stability of redox-active Re-188. Specific aim 2 links these optimized ligands to melanin-binding peptides and investigates the radiolabeling efficiency, Re-188 stability, and the in vitro and in vivo biological behavior of the peptide conjugates. Aim 3 investigates the impact of radiolanthanides that possess a range of half-lives, beta-energies, dose rates and penetration depths on biodistribution and therapeutic efficacy. The outcome of the entire project will be an expansion of the selection of radionuclides for radiotherapy of melanoma that will consider tumor size, density and disposition in the body as well as the mAb or peptide residence time in the body. This project also offers the opportunity to develop the PI's research status. The in vitro and in vivo assays learned in this project will add to her sound inorganic chemistry and synthetic skills to increase her competitiveness to apply for R01 funding in the area of inorganic radiotherapy at the end of 3 years.